The proposed research is designed to determine the effect of myocardial ischemia on the activity of energy producing metabolic pathways and the control mechanisms involved in these pathways as well as to assess the influence of metabolic rate on postischemic mechanical function. Depressed mechanical function following myocardial ischemia is associated with reduced tissue concentrations of adenosine triphosphate, increased reliance on glucose metabolism for energy production and an apparent decrease in the efficiency of energy production from oxidation of substrates. An understanding of the mechanisms responsible for such changes may provide insight into processes leading to irreversible cell damage. Myocardial ischemia will be studied in isolated perfused working hearts and the effect of chronic hypoxia will be determined in cultured heart cells. Altered glucose and fatty acid metabolism during ischemia could result from changes in the activity of specific enzymes within metabolic pathways. This activity may be modified by the presence of inhibitors, the amount of enzyme or the availability of co-factors. Studies of the development of control processes under aerobic and hypoxic conditions would provide insight into how myocardial energy production can be modified. Such studies could lead to the development of therapeutic interventions to decrease cellular damage during myocardial ischemia and enhance recovery of reperfused ischemic myocardium.